CN115322143B - Preparation method of 4-tert-butyl piperidine formate hydrochloride - Google Patents
Preparation method of 4-tert-butyl piperidine formate hydrochloride Download PDFInfo
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- CN115322143B CN115322143B CN202210877302.1A CN202210877302A CN115322143B CN 115322143 B CN115322143 B CN 115322143B CN 202210877302 A CN202210877302 A CN 202210877302A CN 115322143 B CN115322143 B CN 115322143B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a preparation method of 4-tert-butyl piperidine formate hydrochloride, and belongs to the field of synthesis of pharmaceutical intermediates. The method takes 4-piperidinecarboxylic acid as a raw material to synthesize 4-tert-butyl piperidinecarboxylic acid hydrochloride through salification reaction and esterification reaction under the condition of pressurization. The invention provides a preparation method of 4-tert-butyl piperidine formate hydrochloride, which has the advantages of controllable reaction process, simple operation, high yield and good product purity.
Description
Technical Field
The invention belongs to the field of synthesis of pharmaceutical intermediates, and relates to a preparation method of 4-tert-butyl piperidine formate hydrochloride.
Background
Tert-butyl 4-piperidinecarboxylate hydrochloride of the formula: c (C) 10 H 20 ClNO 2 Molecular weight: 221.72, cas:892493-65-1, the chemical structural formula is shown as follows:
the 4-tert-butyl piperidine carboxylate hydrochloride is an important intermediate for synthesizing antitumor drugs, urinary system drugs and cardiovascular and cerebrovascular drugs, the two synthesis routes are mainly two at present, the first route (WO 2015085132) is to use 4-piperidine formic acid as a raw material to synthesize N-Cbz-piperidine-4-carboxylic acid, then use an acylating reagent to convert the carboxylic acid into acyl chloride, then react with tert-butyl alcohol to obtain N-CBz-4-tert-butyl piperidine carboxylate, finally remove CBz and salify to obtain the 4-tert-butyl piperidine carboxylate hydrochloride, and the specific synthesis route is as follows:
the method is characterized in that 4-piperidinecarboxylic acid is used as a raw material to synthesize 4-tert-butyl piperidinecarboxylic acid hydrochloride through 5 steps of reaction, the reaction route is long, the overall yield is low, the acid chloride and tert-butyl alcohol react in one step, the steric hindrance of the tert-butyl alcohol is large, the yield is less than 60%, CBz is used for protecting amine, and then protecting groups are removed, so that the reaction steps are increased, and the overall yield is reduced.
Patent JP2009161510 reports a process for synthesizing tert-butyl 4-piperidinecarboxylate by a one-step method through the addition of 4-piperidinecarboxylic acid and isobutene under the catalysis of acid, and then the process is salified with hydrochloric acid to obtain tert-butyl 4-piperidinecarboxylate hydrochloride, wherein the specific synthetic route is as follows:
the route is a brand new synthetic route, the isobutene is adopted to be added under the catalysis of acid, the tert-butyl 4-piperidinecarboxylate is synthesized by a one-step method, but the 4-piperidinecarboxylate is difficult to dissolve in an organic solvent, the reaction belongs to a gas-liquid heterogeneous reaction, the yield is only about 10 percent, the purification is difficult, and the industrialization is difficult to realize.
Disclosure of Invention
The invention provides a preparation method of 4-tert-butyl piperidine formate hydrochloride aiming at the defects in the prior art.
To increase the solubility of 4-piperidinecarboxylic acid, the reaction is carried out under a certain pressure environment. The invention takes 4-piperidine formic acid as raw material, under the condition of pressurization, the raw material is heated in concentrated hydrochloric acid for 4 hours, the temperature is reduced, the solvent is added, the solid is separated out, and the 4-piperidine hydrochloride is obtained by filtration; adding 4-piperidine hydrochloride into solvent, adding catalyst, and dripping Boc 2 O anhydride reacts at a certain temperature and pressure to generate 4-tert-butyl piperidine formate hydrochloride, and the specific synthetic route is as follows:
s1, adding 4-piperidinecarboxylic acid and concentrated hydrochloric acid into an autoclave, introducing nitrogen, maintaining a certain pressure, reacting for 4 hours at 85-90 ℃, cooling to room temperature, recovering to normal pressure, adding a solvent, cooling to separate out solid, and filtering to obtain 4-piperidinecarboxylic acid hydrochloride;
s2, adding 4-piperidine hydrochloride and a solvent into an autoclave, adding a catalyst and adding Boc 2 O anhydride at a certain temperatureThe reaction is carried out under the condition of degree and pressure to generate the tert-butyl 4-piperidinecarboxylate hydrochloride.
The solvent in the step S1 is one or more of acetone, tetrahydrofuran, acetonitrile, methanol, ethanol, tertiary butanol and dimethyl sulfoxide, preferably methanol, and the solvent amount is 3 times of the mass of 4-piperidinecarboxylic acid; the pressure is 0.3-0.5MPa;
the solvent in the step S2 is a mixture of tetrahydrofuran, water, acetonitrile and water, 1, 4-dioxane, water, acetone and water, and the volume ratio of the organic solvent to the water is 1:0.5-1, preferably acetonitrile and water; the catalyst is one of 4-dimethylaminopyridine and 4-pyrrolidinyl pyridine, preferably 4-dimethylaminopyridine; the reaction temperature is 50-60 ℃; the reaction pressure is 0.2-0.4MPa.
The invention has the beneficial effects that:
(1) The solubility of the 4-piperidinecarboxylic acid and the 4-piperidinecarboxylic acid hydrochloride is increased by the reaction under a certain pressure, so that the reaction time is greatly shortened;
(2) The reaction route section can synthesize the tert-butyl 4-piperidinecarboxylate by only 2 steps of reaction;
(3) The product purity is good, the yield is high, the total yield of the two-step reaction is 80%, and the product purity is more than 99%.
Detailed Description
Example 1:
4-piperidinecarboxylic acid (2 kg) is added into a 10L high-pressure reaction kettle, concentrated hydrochloric acid (2 kg) is added, nitrogen is introduced, the pressure of the reaction system is maintained at 0.5MPa, the reaction is carried out for 4 hours at 90 ℃, the reaction system is cooled to room temperature of 20-25 ℃, normal pressure is recovered, methanol (3 kg) is added, the temperature is reduced to 5-10 ℃, and solid is separated out. Filtration, washing of the filter cake with methanol (1 kg) and drying gave a white solid in 95% yield.
4-piperidine hydrochloride (1 kg), acetonitrile (2 kg), water (1 kg), boc anhydride (1.4 kg) and 4-dimethylaminopyridine (40 g) are added into a 10L high-pressure reaction kettle, nitrogen is introduced, the pressure of a reaction system is maintained at 0.4MPa, the reaction is carried out for 2 hours at 60 ℃, the temperature is cooled to 20-25 ℃, the normal pressure is recovered, the temperature is reduced to 5-10 ℃ continuously, solids are separated out, the solid is filtered, a filter cake is stirred and washed for 1 hour by ethyl acetate (3 kg), the white solid is obtained after filtration and drying, and the yield is 84% and the purity is 99%.
Example 2:
4-piperidinecarboxylic acid (2 kg) is added into a 10L high-pressure reaction kettle, concentrated hydrochloric acid (2 kg) is added, nitrogen is introduced, the pressure of a reaction system is maintained at 0.3MPa, the reaction is carried out for 4 hours at 85 ℃, the reaction system is cooled to room temperature of 20-25 ℃, normal pressure is recovered, acetone (3 kg) is added, the temperature is reduced to 5-10 ℃, and solid is separated out. Filtration, washing of the filter cake with acetone (1 kg) and drying gave a white solid in 93% yield.
4-piperidine hydrochloride (1 kg), acetone (2 kg), water (2 kg), boc anhydride (1.4 kg) and 4-dimethylaminopyridine (40 g) are added into a 10L high-pressure reaction kettle, nitrogen is introduced, the pressure of a reaction system is maintained at 0.2MPa, the reaction is carried out for 2 hours at 50 ℃, the temperature is cooled to 20-25 ℃, the normal pressure is recovered, the temperature is reduced to 5-10 ℃ continuously, solids are separated out, the solid is filtered, a filter cake is stirred and washed for 1 hour by ethyl acetate (3 kg), the white solid is obtained after filtration and drying, and the yield is 80.2% and the purity is 99%.
Example 3:
4-piperidinecarboxylic acid (2 kg) is added into a 10L high-pressure reaction kettle, concentrated hydrochloric acid (2 kg) is added, nitrogen is introduced, the pressure of a reaction system is maintained at 0.4MPa, the reaction is carried out for 4 hours at 90 ℃, the reaction system is cooled to room temperature of 20-25 ℃, normal pressure is recovered, dimethyl sulfoxide (3 kg) is added, the temperature is reduced to 5-10 ℃, and solids are separated out. Filtration, washing of the filter cake with dimethyl sulfoxide (1 kg) and drying gave a white solid in 95% yield.
4-piperidine hydrochloride (1 kg), tetrahydrofuran (2 kg), water (1 kg), boc anhydride (1.4 kg) and 4-pyrrolidinyl pyridine (45 g) are added into a 10L high-pressure reaction kettle, nitrogen is introduced, the pressure of the reaction system is maintained at 0.3MPa, the reaction is carried out for 2 hours at 60 ℃, the temperature is cooled to 20-25 ℃, the normal pressure is recovered, the temperature is reduced to 5-10 ℃ continuously, solids are separated out, the solid is filtered, a filter cake is stirred and washed for 1 hour by ethyl acetate (3 kg), the white solid is obtained after filtration and drying, and the yield is 82.5% and the purity is 99%.
Example 4:
4-piperidinecarboxylic acid (2 kg) is added into a 10L normal pressure reaction kettle, concentrated hydrochloric acid (2 kg) is added, the reaction is carried out for 4 hours at 90 ℃, the temperature is cooled to be between 20 and 25 ℃, the normal pressure is recovered, methanol (3 kg) is added, the temperature is reduced to be between 5 and 10 ℃, and solid is separated out. Filtration, washing of the filter cake with methanol (1 kg) and drying gave a white solid in 73% yield.
4-piperidine hydrochloride (1 kg), acetonitrile (2 kg), water (1 kg), boc anhydride (1.4 kg) and 4-dimethylaminopyridine (40 g) are added into a 10L reaction kettle, the mixture is reacted for 2 hours at 60 ℃, the mixture is cooled to room temperature of 20-25 ℃, the temperature is continuously reduced to 5-10 ℃, solids are separated out, the mixture is filtered, a filter cake is stirred and washed by ethyl acetate (3 kg) for 1 hour, the mixture is filtered and dried to obtain white solids, and the yield is 48 percent and the purity is 98 percent.
Example 5:
4-piperidine hydrochloride (1 kg), acetonitrile (2 kg), water (1 kg) and Boc anhydride (1.4 kg) are added into a 10L high-pressure reaction kettle, nitrogen is introduced, the pressure of a reaction system is maintained at 0.4MPa, the reaction is carried out at 60 ℃ for 2 hours, the temperature is cooled to room temperature to 20-25 ℃, the normal pressure is recovered, the temperature is continuously reduced to 5-10 ℃, solids are separated out, the filtration is carried out, a filter cake is stirred and washed by ethyl acetate (3 kg) for 1 hour, the filtration and the drying are carried out, and white solids are obtained, wherein the yield is 42.8% and the purity is 88%.
Example 6:
A1L autoclave was charged with 4-piperidinecarboxylic acid (100 g), 1, 4-dioxane (300 g), concentrated sulfuric acid (10 g) and isobutylene were introduced, and the reaction was carried out at a temperature of 50℃under a pressure of 0.5MPa for 3 hours, and the conversion of 4-piperidinecarboxylic acid was 9% by means of a sample-controlled analysis.
While the foregoing describes the embodiments of the present invention, it should be understood that the present invention is not limited to the embodiments, and that various modifications and changes can be made by those skilled in the art without any inventive effort.
Claims (2)
1. The preparation method of the tert-butyl 4-piperidinecarboxylate hydrochloride is characterized by comprising the following synthetic routes:
s1, adding 4-piperidinecarboxylic acid and concentrated hydrochloric acid into an autoclave, introducing nitrogen, maintaining the reaction pressure, reacting at 85-90 ℃, cooling to room temperature, recovering to normal pressure, adding a solvent, cooling to separate out solid, and filtering to obtain 4-piperidinecarboxylic acid hydrochloride, wherein the reaction pressure is 0.3-0.5MPa;
s2, adding 4-piperidine hydrochloride and a solvent into an autoclave, adding a catalyst and adding Boc 2 O, maintaining the reaction temperature and the reaction pressure to generate the tert-butyl 4-piperidinecarboxylate hydrochloride, wherein the solvent is a mixture of tetrahydrofuran, acetonitrile and water, and acetone and water, the volume ratio of the tetrahydrofuran, acetonitrile or acetone solvent to water is 1:0.5-1, the catalyst is one of 4-dimethylaminopyridine and 4-pyrrolidinylpyridine, the reaction temperature is 50-60 ℃, and the reaction pressure is 0.2-0.4MPa.
2. The method for preparing tert-butyl 4-piperidinecarboxylate hydrochloride according to claim 1, wherein the solvent in the step S1 is one or more of acetone, tetrahydrofuran, acetonitrile, methanol, ethanol, tert-butanol and dimethyl sulfoxide.
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| CN202210877302.1A CN115322143B (en) | 2022-07-21 | 2022-07-21 | Preparation method of 4-tert-butyl piperidine formate hydrochloride |
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| GB0421908D0 (en) * | 2004-10-01 | 2004-11-03 | Angeletti P Ist Richerche Bio | New uses |
| WO2010111058A1 (en) * | 2009-03-23 | 2010-09-30 | Merck Sharp & Dohme Corp. | P2x3, receptor antagonists for treatment of pain |
| TR201807740T4 (en) * | 2012-12-07 | 2018-06-21 | Vertex Pharma | 2-amino-6-fluoro-n- (5-fluoro-4- (4- (4- (oxetan-3-yl) piperazine-1-carbonyl) piperidin-1-yl) pyridine-3- as an ATR kinase inhibitor yl) pyrazolo [1,5alf a] pyrimidine-3-carboxamide. |
| CN108239021B (en) * | 2016-12-27 | 2021-04-06 | 瑞博(杭州)医药科技有限公司 | Trifluoromethylation process of bromopyridine and derivatives thereof |
| TWI785474B (en) * | 2020-01-22 | 2022-12-01 | 大陸商北京加科思新藥研發有限公司 | Novel heterocyclic compounds useful as selective aurora a inhibitors |
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